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Mutations in APC, Kirsten-ras, and p53--alternative genetic pathways to colorectal cancer.
Proc Natl Acad Sci U S A. 2002 Jul 09; 99(14):9433-8.PN

Abstract

Colorectal cancer is one of the most significant causes of cancer death. A genetic model for colorectal cancer has been proposed in which the sequential accumulation of mutations in specific genes, including adenomatous polyposis coli (APC), Kirsten-ras (K-ras), and p53, drives the transition from healthy colonic epithelia through increasingly dysplastic adenoma to colorectal cancer. We have characterized tumor mutation spectra in a large cohort of colorectal cancer patients. In marked contrast to the predictions of the sequential model of mutation accumulation, only 6.6% of tumors were found to contain mutations in APC, K-ras, and p53, with 38.7% of tumors containing mutations in only one of these genes. The most common combination of mutations was p53 and APC (27.1%), whereas mutations in both p53 and K-ras were extremely rare. Statistical analysis (two-sided Fisher's exact test) confirmed that mutations in K-ras and p53 co-occurred less frequently than expected by chance (P < 0.01, Fisher's exact test). This finding suggests that these mutations lie on alternate pathways of colorectal tumor development. The heterogeneous pattern of tumor mutations in our patient cohort suggests that multiple alternative genetic pathways to colorectal cancer exist and that the widely accepted genetic model of cancer development is not representative of the majority of colorectal tumors.

Authors+Show Affiliations

Cancer Research United Kingdom Molecular Pharmacology Unit, Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12093899

Citation

Smith, Gillian, et al. "Mutations in APC, Kirsten-ras, and P53--alternative Genetic Pathways to Colorectal Cancer." Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 14, 2002, pp. 9433-8.
Smith G, Carey FA, Beattie J, et al. Mutations in APC, Kirsten-ras, and p53--alternative genetic pathways to colorectal cancer. Proc Natl Acad Sci USA. 2002;99(14):9433-8.
Smith, G., Carey, F. A., Beattie, J., Wilkie, M. J., Lightfoot, T. J., Coxhead, J., Garner, R. C., Steele, R. J., & Wolf, C. R. (2002). Mutations in APC, Kirsten-ras, and p53--alternative genetic pathways to colorectal cancer. Proceedings of the National Academy of Sciences of the United States of America, 99(14), 9433-8.
Smith G, et al. Mutations in APC, Kirsten-ras, and P53--alternative Genetic Pathways to Colorectal Cancer. Proc Natl Acad Sci USA. 2002 Jul 9;99(14):9433-8. PubMed PMID: 12093899.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutations in APC, Kirsten-ras, and p53--alternative genetic pathways to colorectal cancer. AU - Smith,Gillian, AU - Carey,Francis A, AU - Beattie,Julie, AU - Wilkie,Murray J V, AU - Lightfoot,Tracy J, AU - Coxhead,Jonathan, AU - Garner,R Colin, AU - Steele,Robert J C, AU - Wolf,C Roland, Y1 - 2002/07/01/ PY - 2002/7/3/pubmed PY - 2002/8/9/medline PY - 2002/7/3/entrez SP - 9433 EP - 8 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 99 IS - 14 N2 - Colorectal cancer is one of the most significant causes of cancer death. A genetic model for colorectal cancer has been proposed in which the sequential accumulation of mutations in specific genes, including adenomatous polyposis coli (APC), Kirsten-ras (K-ras), and p53, drives the transition from healthy colonic epithelia through increasingly dysplastic adenoma to colorectal cancer. We have characterized tumor mutation spectra in a large cohort of colorectal cancer patients. In marked contrast to the predictions of the sequential model of mutation accumulation, only 6.6% of tumors were found to contain mutations in APC, K-ras, and p53, with 38.7% of tumors containing mutations in only one of these genes. The most common combination of mutations was p53 and APC (27.1%), whereas mutations in both p53 and K-ras were extremely rare. Statistical analysis (two-sided Fisher's exact test) confirmed that mutations in K-ras and p53 co-occurred less frequently than expected by chance (P < 0.01, Fisher's exact test). This finding suggests that these mutations lie on alternate pathways of colorectal tumor development. The heterogeneous pattern of tumor mutations in our patient cohort suggests that multiple alternative genetic pathways to colorectal cancer exist and that the widely accepted genetic model of cancer development is not representative of the majority of colorectal tumors. SN - 0027-8424 UR - https://www.unboundmedicine.com/medline/citation/12093899/Mutations_in_APC_Kirsten_ras_and_p53__alternative_genetic_pathways_to_colorectal_cancer_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&amp;pmid=12093899 DB - PRIME DP - Unbound Medicine ER -